Lung transplantation is an important treatment option for patients with advanced lung diseases. Indeed, the majority of patients can expect excellent functional recovery and improved quality-of-life after transplant. Despite this improvement in early survival and function, though, obliterative bronchiolitis (OB), a generally progressive loss of small airway function, gravely threatens the long-term outlook for lung transplant recipients (LTRs). OB and its clinical correlate, bronchiolitis obliterans syndrome (BOS), is the most common chronic complication, affecting the majority of patients who survive 5 years after transplantation. The key clinical feature of BOS is the development of airway obstruction diagnosed with pulmonary function testing (PFT). However, PFT is a global lung function measure and does not provide information about regional disease involvement or early BOS. To prevent or delay onset of BOS, it would be useful to directly assess local regional development of OB. The regional OB map would allow us to evaluate mechanisms of BOS, disease progression, and provide a tool for image-guided biopsy or treatment at specific lung regions to improve the efficacy of an early therapeutic intervention. Conventional CT or MR imaging is limited, however, and does not allow a simultaneous evaluation of the regional ventilation and morphologic changes associated with early changes in BOS. Thus, we have developed a novel xenon CT regional ventilation imaging technique and quantitative method for lung morphology analysis, and propose that these new tools are crucial to investigate both functional and morphological changes in transplanted lungs and the underlying mechanisms involved in development and progression of allograft dysfunction in LTRs. The primary objective is to evaluate our xenon CT imaging technique to assess regional ventilation and morphological changes, and to associate these changes with pulmonary function testing and BOS progression. The proposed research is innovative in that we have developed a novel xenon CT lung imaging technique and a new, efficient and reliable semi-automated interactive method for segmentation. Our central hypothesis is that xenon CT can be used to quantify changes in lung regional ventilation and morphology and associate these changes with pulmonary function and disease progression. The Specific Aims are (1) to develop and evaluate xenon CT imaging biomarkers and compare the cross-sectional differences between BOS stages in lung transplant recipients; (2) to determine whether longitudinal changes in xenon CT imaging biomarkers are associated with longitudinal changes in pulmonary function measures in patients with early BOS; and (3) to compare lung segmental abnormalities of xenon CT imaging biomarkers with histopathological abnormalities of segmental airways in selected patients. Completion of these aims will quantify cross-sectional (Aim 1) and longitudinal (Aim 2) associations between the xenon CT imaging biomarkers and pulmonary function, providing a key first step in establishing their utility as regional imaging markers for BOS progression in transplanted lungs.